Delivery catheter for and method of delivering an implant, for example, bronchoscopically implanting a marker in a lung

ABSTRACT

Systems and methods for treating a lung of a lung of a patient. One embodiment of a method comprises positioning a leadless marker in the lung of the patient relative to the target, and collecting position data of the marker. This method further comprises determining the location of the marker in an external reference frame outside the patient based on the collected position data, and providing an objective output in the external reference frame that is responsive to movement of the marker. The objective output is provided at a frequency (i.e., periodicity) that results in a clinically acceptable tracking error. In addition, the objective output can also be provided at least substantially contemporaneously with collecting the position data used to determine the location of the marker.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.13/877,257, filed on Sep. 16, 2013, which is a 371 U.S. national phaseapplication of PCT/US2011/054656, filed on Oct. 3, 2011, which claimsthe benefit of U.S. Provisional Patent Application No. 61/389,184, filedOct. 1, 2010, all of which are incorporated herein by reference theirentirety.

TECHNICAL FIELD

The present invention is directed toward bronchoscopically implantingmarkers in the lung of a patient and more particularly, toward apre-loaded delivery catheter with a marker wherein the marker includesan improved anti-migration device.

BACKGROUND

Radiation therapy has become a significant and highly successful processfor treating prostate cancer, lung cancer, brain cancer and many othertypes of localized cancers. Radiation therapy procedures generallyinvolve (a) planning processes to determine the parameters of theradiation (e.g., dose, shape, etc.), (b) patient setup processes toposition the target at a desired location relative to the radiationbeam, (c) radiation sessions to irradiate the cancer, and (d)verification processes to assess the efficacy of the radiation sessions.Many radiation therapy procedures require several radiation sessions(i.e., radiation fractions) over a period of approximately 5-45 days.

To improve the treatment of localized cancers with radiotherapy, it isgenerally desirable to increase the radiation dose because higher dosesare more effective at destroying most cancers. Increasing the radiationdose, however, also increases the potential for complications to healthytissues. The efficacy of radiation therapy accordingly depends on boththe total dose of radiation delivered to the tumor and the dose ofradiation delivered to normal tissue adjacent to the tumor. To protectthe normal tissue adjacent to the tumor, the radiation should beprescribed to a tight treatment margin around the target such that onlya small volume of healthy tissue is irradiated. For example, thetreatment margin for prostate cancer should be selected to avoidirradiating rectal, bladder and bulbar urethral tissues. Similarly, thetreatment margin for lung cancer should be selected to avoid irradiatinghealthy lung tissue or other tissue. Therefore, it is not only desirableto increase the radiation dose delivered to the tumor, but it alsodesirable to mitigate irradiating healthy tissue.

One difficulty of radiation therapy is that the target often moveswithin the patient either during or between radiation sessions. Forexample, tumors in the lungs move during radiation sessions because ofrespiration motion and cardiac functions (e.g., heartbeats andvasculature constriction/expansion). To compensate for such movement,the treatment margins are generally larger than desired so that thetumor does not move out of the treatment volume. However, this is not adesirable solution because the larger treatment margins may irradiate alarger volume of normal tissue.

Localization and/or tracking of markers, such as gold fiducials orelectromagnetic transponders, implanted in proximity to the target ortumor may enable increased tumor radiation and decreased healthy tissueirradiation. However, fluoroscopic imaging of implanted gold fiducialsis limited by high doses of non-therapeutic imaging radiation, expensivefluoroscopic equipment, subjective image interpretation and poor implantstability.

Another challenge in radiation therapy is accurately aligning the tumorwith the radiation beam. Current setup procedures generally alignexternal reference markings on the patient with visual alignment guidesfor the radiation delivery device. For an example, a tumor is firstidentified within the patient using an imaging system (e.g., X-ray,computerized tomography (CT), magnetic resonance imaging (MRI), orultrasound system). The approximate location of the tumor relative totwo or more alignment points on the exterior of the patient is thendetermined. During setup, the external marks are aligned with areference frame of the radiation delivery device to position thetreatment target within the patient at the beam isocenter of theradiation beam (also referenced herein as the machine isocenter).Conventional setup procedures using external marks are generallyinadequate because the target may move relative to the external marksbetween the patient planning procedure and the treatment session and/orduring the treatment session. As such, the target may be offset from themachine isocenter even when the external marks are at theirpredetermined locations for positioning the target at the machineisocenter. Reducing or eliminating such an offset is desirable becauseany initial misalignment between the target and the radiation beam willlikely cause normal tissue to be irradiated. Moreover, if the targetmoves during treatment because of respiration, organ filling, or cardiacconditions, any initial misalignment will likely further exacerbateirradiation of normal tissue. Thus, the day-by-day and moment-by-momentchanges in target motion have posed significant challenges forincreasing the radiation dose applied to patients.

Conventional setup and treatment procedures using external marks alsorequire a direct line-of-sight between the marks and a detector. Thisrequirement renders these systems useless for implanted markers ormarkers that are otherwise in the patient (i.e., out of theline-of-sight of the detector and/or the light source). Thus,conventional optical tracking systems have many restrictions that limittheir utility in medical applications. Thus, there is a continuing needfor improved localization and tracking of markers, including an improvedmethod of placing the marker and an improved system of preventingmovement of the marker once placed.

Tumor target localization has been demonstrated utilizing implantedmarkers such as gold fiducials (balls and cylinders) and electromagnetictransponders. One method of placement for these markers in the lung isto deliver them into the bronchus/bronchioles of the lung and thenforce-fit the markers into the appropriate diameter bronchiole near thetreatment target location. The implant location that permits a force-fitof the markers is likely not the most desired location, but one thatsimply accommodates the force fit. Additionally, the act of breathing,which effects a small enlargement/contraction cycle of the bronchioles,may dislodge the marker from its desired location. Many inhaled drugsalso effect changes in the diameter of the bronchioles. Further, actionssuch as coughing, which typically originate in the alveolar structuresnear the lung periphery, serve to force the markers from their desiredlocations to locations closer to the trachea.

Thus implanted marker usage for localization and tracking of lung tissuetargets has proven challenging due to marker migration issues. Sincemarkers are surrogates for the actual treatment target position, thereis a need to minimize potential for marker migration throughout theentire course of radiation therapy (from treatment planning to lastradiation fraction application). Initial positioning and maintenance ofmarker location should desirably be accomplished independent ofbronchus/bronchiole size. The position of the marker needs to remainstationary regardless of feature changes within the bronchioles. Amultiplicity of devices, methods, and systems are listed to accomplishthat task.

The airways in the lungs anatomically constitute an extensive network ofconduits that reach all lung areas and lung tissues. Air enters theairways through the nose or mouth, travels through the trachea and intothe bronchi and bronchioli of the lunch. The lungs are covered by athink membrane called the pleura. Because of these physiologicalcharacteristics of the airways, a marker placed in bronchi andbronchioli may cause pneumothorax when implanted, thus, there is a needfor a new and improved device, system, and method for implanting amarker in the region proximate to a tumor or other lesion in the lung.

One recent method for locating a target implanted within the bodyincludes a wireless implantable marker configured to be implantedsurgically or percutaneously into a human body relative to a targetlocation. The markers include a casing and a signal element in thecasing that wirelessly transmits location signals in response to anexcitation energy. One concern of using implanted markers in softtissues, bronchi or bronchioli is that the markers may move within thepatient after implantation. To resolve this concern, Calypso MedicalTechnologies, Inc. previously developed several anchors and fastenersfor securing the markers to soft tissue structures, as disclosed in U.S.application Ser. No. 10/438,550, which is incorporated herein byreference. Although these anchors may work for percutaneous or surgicalimplantation, they may be improved for bronchoscopic applications.Therefore, it would be desirable to further develop markers forbronchoscopic deployment and implantation.

BRIEF DESCRIPTION OF THE DRAWINGS

In the drawings, identical reference numbers identify similar elementsor acts. The sizes and relative positions of elements in the drawingsare not necessarily drawn to scale. For example, the shapes of variouselements and angles are not drawn to scale, and some of these elementsare arbitrarily enlarged and positioned to improve drawing legibility.Further, the particular shapes of the elements as drawn, are notintended to convey any information regarding the actual shape of theparticular elements, and have been solely selected for ease ofrecognition in the drawings.

FIG. 1A is an isometric view of a bronchoscopic catheter assembly and astorage and transportation device configured in accordance with anembodiment of the present technology.

FIG. 1B is an enlarged isometric view of the bronchoscopic catheterassembly of FIG. 1A with a marker loaded in the catheter assemblyconfigured in accordance with an embodiment of the present technology.

FIGS. 1C and 1D are an isometric view and an exploded isometric view,respectively, of a package carrying the bronchoscopic catheter assemblyof FIGS. 1A and 1B in accordance with an embodiment of the presenttechnology.

FIG. 1E is a partial cut-away side view of a delivery device configuredin accordance an embodiment of the present technology.

FIG. 2 is a side view of a handle configured in accordance an embodimentof the present technology.

FIGS. 3A-3D are side views of a distal portion of a delivery catheterreleasably retaining a marker in accordance with embodiments of thepresent technology.

FIG. 4 is an isometric cut-away view of a distal portion of a deliverycatheter configured in accordance an embodiment of the presenttechnology.

FIG. 5 is a cross-sectional view of a respiratory system having markerspositioned therein in accordance with an embodiment of the presenttechnology.

FIGS. 6 and 7 are isometric and side views of various aspects of aradiation therapy system configured in accordance an embodiment of thepresent technology.

FIG. 8 is a schematic view illustrating operation of a localizationsystem and markers in accordance with an embodiment of the presenttechnology.

FIG. 9. is a flow diagram for real-time tracking to monitor location andstatus of a target in accordance with an embodiment of the presenttechnology.

FIG. 10A is a CT image illustrating a cross-section of a patient, atarget, and a marker in accordance with an embodiment of the presenttechnology, and FIG. 10B illustrates coordinates of the marker in areference frame of the CT scanner.

FIG. 11 illustrates a user interface showing objective offset values ofa target relative to a machine isocenter in accordance with anembodiment of the present technology.

FIG. 12 illustrates a localization system tracking a target during aradiation session and controlling a radiation delivery source inaccordance with an embodiment of the present technology.

FIG. 13 is an isometric view of an anchorable marker assembly configuredin accordance with an embodiment of the present technology.

FIGS. 14A and 14B are a side view and a partial cut-away isometric view,respectively, of an anchorable marker assembly configured in accordancewith an embodiment of the present technology.

FIG. 15 is an exploded isometric view of the anchorable marker assemblyof FIGS. 14A and 14B.

FIGS. 16A-16C are isometric views of a delivery catheter with apre-loaded anchorable marker assembly in a loaded state (FIGS. 16A and16 b) and a deployed state (FIG. 16C) in accordance with an embodimentof the present technology.

FIGS. 17A and 17B are isometric views of a delivery catheter with apre-loaded anchorable marker assembly in a loaded state and a deployedstate, respectively, in accordance with another embodiment of thepresent technology.

FIGS. 18A and 18B are isometric views of a delivery catheter with apre-loaded anchorable marker assembly in a loaded state and a deployedstate, respectively, in accordance with yet another embodiment of thepresent technology.

FIGS. 19A and 19B are isometric views of a delivery catheter with apre-loaded anchorable marker assembly in a loaded state and a deployedstate, respectively, in accordance with a further embodiment of thepresent technology.

FIGS. 20A and 20B are isometric views of a delivery catheter with apre-loaded anchorable marker assembly in a loaded state and a deployedstate, respectively, in accordance with an additional embodiment of thepresent technology.

FIGS. 21A and 21B are isometric views of a delivery catheter with apre-loaded anchorable marker assembly in a loaded state and a deployedstate, respectively, in accordance with yet another embodiment of thepresent technology.

FIGS. 22A and 22B are isometric views of a delivery catheter with apre-loaded anchorable marker assembly in a loaded state and a deployedstate, respectively, in accordance with still another embodiment of thepresent technology.

FIGS. 23A and 23B are isometric views of a delivery catheter with apre-loaded anchorable marker assembly in a loaded state and a deployedstate, respectively, in accordance with an additional embodiment of thepresent technology.

FIGS. 24A-24D are cross-sectional and end views of anchorable assemblieshaving various loading and unloading configurations in accordance withembodiments of the present technology.

FIGS. 25A-25D are cross-sectional views illustrating various positivestops that provide controlled deployment in accordance with embodimentsof the present technology.

FIG. 26 is a side view of multiple anchorable marker assemblies in aninterconnected configuration configured in accordance with an embodimentof the present technology.

DETAILED DESCRIPTION

In the following description, certain specific details are set forth inorder to provide a thorough understanding of various embodiments of theinvention. However, one skilled in the relevant art will recognize thatthe invention may be practiced without one or more of these specificdetails, or with other methods, components, materials, etc. In otherinstances, well-known structures associated with the system, thebronchoscope catheter assembly, the marker, the anti-migration deviceand/or the storage device have not been shown or described in detail toavoid unnecessarily obscuring descriptions of the embodiments of theinvention.

Several embodiments and features of a bronchoscopic catheter assembly, amarker or a marker with anchors in accordance with embodiments of theinvention are set forth and described in the Figures. In otherembodiments of the invention, the markers can include additional ordifferent features than those shown in the Figures. Additionally,several embodiments of markers in accordance with the invention may notinclude all the features shown in these Figures. For the purposes ofbrevity, like reference numbers refer to similar or identical componentsof the markers in the Figures. Additionally, throughout thespecification, claims, and drawings, the term “proximal” means nearestthe trachea, and “distal” means nearest the alveoli.

The headings provided herein are for convenience only and do notinterpret the scope or meaning of the claimed invention.

A. OVERVIEW

The following disclosure describes several embodiments of wirelessmarkers configured to be implanted and anchored within the lung of ahuman in a manner that prevents the markers from migrating from theimplantation site. The marker is configured to reduce pneumothorax andmay further be configured to include an anchor or anti-migration device.

According to aspects of the invention, a bronchoscopic catheter assemblyincludes a marker pre-loaded at a distal end of a delivery catheter forbronchoscopically implanting the marker in peripheral airways of thelung. According to further aspects of the invention, a marker storageand loading device for retaining the marker prior to loading in thedistal end of the delivery catheter is provided. The marker can extend aselected distance beyond the distal end of the delivery catheter toprovide a leading end. According to aspects of the invention, the markeris configured at the leading end to reduce pneumothorax. According tofurther aspects of the invention, the marker includes an integralanti-migration or anchoring device for preventing migration of themarker after placement of the marker in the lung. According to stillfurther aspects of the invention, an anti-migration device is separatefrom the marker and positioned adjacent to the deployed marker toprevent migration of the marker in the lung after placement. Accordingto still further aspects of the invention, the marker is shaped andsized to reduce migration.

According to aspects of the invention, a marker for use in thebronchoscopic catheter assembly for localizing a target of a patientcomprises a casing, a magnetic transponder at least partially receivedin the casing, and an anchor carried by the casing. The casing is abiocompatible barrier configured to be implanted in the patient. Thecasing can be a generally cylindrical capsule that is sized to fitwithin a catheter of a bronchoscope for bronchoscopic implantation, butthe casing can have other geometric shapes, sizes, and configurations inother applications. For example, the casing can be larger for implantingthe marker in the bronchus. The magnetic transponder produces awirelessly transmitted magnetic field in response to a wirelesslytransmitted excitation energy. The magnetic transponder can furthercomprise a magnetic core, a coil wrapped around the core, and acapacitor coupled to the coil. The anchor, which can project from thecasing, be integral to the casing, or be independent from the casing,secures the marker to an anatomical structure once the marker has beendeployed from the bronchoscopic catheter assembly to prevent the markerfrom moving from the implantation site. According to aspects, the anchormay be detached from the marker. In another embodiment, the marker maybe secured to the anatomical structure by mechanical members or chemicalattributes.

According to further aspects, an anchorable marker configured forbronchoscopic implantation for localizing a target of a patientcomprises a casing, a transponder that produces a wirelessly transmittedmagnetic field in response to a wirelessly transmitted excitation field,and an anchor partially embedded within the casing. The anchor canfurther be configured for bronchoscopic implantation and have a shapeand/or material that pierces, engages or otherwise interfaces with theanatomical anchoring site such that the marker cannot be easilydislodged. Alternatively, the casing is shaped to reduce migration ofthe marker, for example, the casing may be wedge shaped, include a hook,or have a surface texture.

The invention further includes methods for manufacturing and usingmarkers with anchors. One embodiment of such a method comprisesproviding a transponder that produces a wirelessly transmitted magneticfield in response to a wirelessly transmitted excitation field andforming a casing around the transponder. This method can further includeembedding, attaching or forming an anchor in the casing. In alternativeembodiments, the marker may be a gold fiducial, RFID tag, active markeror electromagnetic marker. In still further alternative embodiments, theanchor can be detached from the marker. In further embodiments, thecasing may be the anchor.

According to one current practice, the marker is forcibly wedged intothe lumen, however, this will work only for limited settings andcircumstances. The marker must be approximately the same size as thelumen at the desired geographic placement location. The luminal wallmust possess the appropriate elastic characteristics to retain theforce-fitted marker. Forces such as those caused by coughing andwheezing serve to dislodge the marker. Potentially, mucous transportsystems in the bronchioles could dislodge a force-fit marker. Inhaleddrugs may serve as broncho-dilators and broncho-constrictors. Further,tumor shrinkage during radiation therapy and/or chemotherapy,diaphragmatic motion, the movement of air, and the various pressureprofiles within the lung may serve to dislodge a positional marker.

Human lungs are located on either side of the heart and occupying alarge portion of the chest cavity from the collarbone to the diaphragm.The lungs are covered by a thin membrane called the pleura. Air travelsto the chest cavity through the trachea, which divides into two bronchi,each of which enters a lung. The bronchi divide and subdivide into anetwork of countless tubules. The smallest tubules, or bronchioles,enter cup-shaped air sacs known as alveoli, which number about 700million in both lungs. In the case of a marker that is force-fit into abronchiole, given that bronchioles decrease in diameter toward the lungperiphery, any marker dislodgement would typically result in the markermoving toward the trachea, since there is no mechanism to force themarker further into the decreasing diameter lumen. So, in the case of aforce fit marker, a solitary secondary plug could serve to secure themarker in place. Feasibly, since the marker should not move further downthe bronchiole structure due to its decreasing luminal diameter, thesecondary securing device would need to provide only a marginal increasein holding capacity to keep the marker in place. It should be noted thatin this case, since the retention device is located on the side closerto the trachea side, it will be located in a diameter that isincrementally larger than that of the marker location.

Dependant upon the specific elastic properties at any specific bronchiallocation, a plurality of devices and methods exist for entrapping amarker in the bronchial lumen. A LRD (luminal retention device) embodiedas a plug can be force fit into a tubular structure such as a bronchus,or other bodily lumen, to trap or hold in place a marker. A LRD rigidplug would rely on the resiliency of the lumen to hold the plug inplace, while a plug constructed of silicone, sponge, or other similarmaterials would inherently possess its own resiliency. Thefibrin-thrombin type adhesives and adhesive blobs could be used to a)build a LRD plug in-place in the lumen to prevent the marker fromdislodging, b) augment the diameter or attach a smaller sized LRD plugto the luminal wall, or c) used to glue the transponder directly to thewall. Cyanoacrylate adhesives could be used in this application as well.A related product, the foamed-matrix biologically-based materialspossess mechanical properties similar to weak plastics prior to beingexposed to body fluids, and could be pre-formed into acceptable shapesto force-fit into a lumen, but would shortly form a soft, biologicallybased plug once established in the mucous of the bronchial tree.

Many shapes can be utilized as an LRD anchor or plug, since the goal isto fixate the marker. Materials many include plastics, metals,adhesives, expandable sponges, and bio-materials (e.g. collagen,connective tissue derivatives). Additional embodiments include: wire orshaped metal “ring”, hex, umbrella, etc. A form resembling a helicalshaped wire spring can be advanced through a small diameter conduit tothe desired location in a compressed state, expanding to the luminaldiameter upon expulsion from the confines of the conduit, trapping themarker on one side. A plurality of materials could be utilized,including, at least, metals, plastics, and matrix materials such ascarbon-fiber.

Further, the internally-springed, radially self-expander marker anchorallows for diametral growth or shrinkage of the lumen in which itresides, without requiring adjustment or positioning. While the devicehas been presented herein as a single anchor, it may be used in pairswithin a lumen to trap a marker between the pair of anchors. As long asthe marker cannot escape through the LRD device toward to the largerbronchiole structures the device should remains stationary and the goalwill be realized.

Consideration should be allowed for delivery of any of the devices aswell. The ability of a device to be delivered in a compact, orcompressed state, is a definite advantage. Further, the ability of adevice to compensate for differences in lumen size and elasticity allowsthe use of a single device for a plurality of lumen sizes and,therefore, lumen locations. To fixate a marker within a lumen, themarker can be forcibly wedged within the lumen, anchored to the luminalwall, entrapped against the luminal wall, anchored to the luminal wallusing a leg of a bifurcation point, entrapped within the lumen by asecond device, or trapped at a specific location within the lumen by theuse of two secondary devices. Combinations of these methods may beemployed as well.

B. CATHETER HAVING A PRELOADED MARKER POSITIONED AT A DISTAL END

FIG. 1A is an isometric view of a bronchoscopic catheter assembly 200for use in a working channel of a bronchoscope (not shown for clarity)and a storage and transportation device 240 having a receiving hoop 246for releasably retaining a delivery catheter 212 during storage andtransportation of the delivery catheter 212 in accordance with anembodiment of the invention. FIG. 1B is an isometric, expanded view ofthe bronchoscopic catheter assembly 200 of FIG. 1A with a marker 220loaded in the distal end 216 of the delivery catheter 212 and thestorage and transportation device 240 cut away to show loading of thedelivery catheter 212 in the receiving hoop 246. As shown in FIGS. 1Aand 1B, the bronchoscopic catheter assembly 200 includes a deliverycatheter 212 having a deployment channel 211 configured to releasablyretain a marker 220 at a distal end 214 of the delivery catheter 212such that the marker 220 extends a selected distance beyond a distal end216 of the delivery catheter 212.

Referring now to FIG. 1A, the storage and transportation device 240 forretaining the bronchoscopic catheter assembly 200 during storage andtransportation is provided. The storage and transportation device 240includes a receiving hoop 246 for releasably retaining the deliverycatheter 212. The storage and transportation device 240 can include ahousing 230 which is configured to releasably retain the receiving hoppin clips 232 a, b. The housing 230 may further include a guide 234and/or an insertion guide assembly for guiding the distal end of thedelivery catheter 212 therein. The housing 244 additionally provides analignment means for mating with the distal end of the catheter whenloading the marker 220 into the catheter as discussed further withrespect to FIG. 5.

Referring now to FIG. 1A, a proximal end 214 of the delivery catheter212 is configured to engage a handle 210 having an actuator 222. Theactuator 222 is moveable between a first position and a second positionalong arrow A. In the second position, the actuator 222 moves towardsand/or abuts a flange 224. The flange 224 is configured to stop movementof the actuator 222 along line A by engaging the actuator 222 on a firstside. On a second side, opposite the first side, the flange 224 retainsthe delivery catheter 212. The flange 224 further includes a sleeve (notshown) for slidably receiving a push wire 218 therein.

The push wire 218 is retained by the body of the catheter and moves withthe actuator 222. The push wire 218 may be a Teflon wire, steel cable,steel wire, Nitanol® or other flexible cable having sufficient rigidityto deploy the marker 220 when the actuator 222 is moved along line A. Asshown in FIG. 3B, the push wire 218 may include a disc shaped end 404for engaging the marker 220. Alternatively, an end 404 of the push wire218 may be an appropriately shaped wire or rod. The end 404 may have adiameter dimension slightly less than the diameter dimension of thechannel 211 to allow the push wire 218 to slide co-axially therein. Thedistal end of the delivery catheter is described in greater detailbelow.

The handle 210 is configured to be moveable by an operator (not shown)and may further be configured to attach to the working channel of thebronchoscope. Referring now to FIG. 2, the handle 210 can include anactuator 322 including a button or flat plate configured to be engagedby a digit of an operator's hand (not shown for purposes of clarity).The actuator 322 abuts the housing 324 to stop axial movement along lineA. As shown in FIG. 2, the handle 210 can include an actuator 322including a ring configured to be engaged by a digit of an operator'shand. As further shown, the housing 326 can be ergonomically shaped tothe hand of a user. Alternative configurations of the actuator canfurther be provided. The handle 210 may further include a lock 326,shown in FIG. 2 on the housing 324, to prevent accidental deployment ofthe marker.

One aspect of several embodiments of the present invention is deliveringor deploying the markers 40 into or at least proximate to a tumorlocated in the lung of the patient. Accordingly, the delivery device canbe a bronchoscope, catheter, or other device configured to pass througha lumen in the respiratory system of the patient. Generally speaking,the delivery device includes a handle and an elongated body attached tothe handle. More specifically, the elongated body includes a proximalsection at the handle and a distal section configured to pass throughlumen in the respiratory system. In many embodiments, the distal sectionof the elongated body is flexible, but in other embodiments the entireelongated body can be flexible or rigid. In operation, the marker issupported by the elongated body at the distal section for deploymentinto the patient. In several embodiments, the delivery device furtherincludes a deployment mechanism that is operable from the handle torelease the marker into the patient. The deployment mechanism can be apush rod that pushes the marker out of the distal section of theelongated body. In an alternative embodiment, the deployment mechanismcan include a cannula and a stylet slidably received in the cannula. Inthis embodiment, the cannula and stylet are configured to move togetherto project distally beyond the distal section of the elongated body, andthen the cannula may be withdrawn proximally relative to the stylet torelease the marker into the patient.

According to still further embodiments, the delivery device can furtherinclude a steering mechanism that is operable from the handle. Thesteering mechanism can include an attachment point at the distal sectionand a slidable member configured to move longitudinally relative to theelongated body. Longitudinal movement of the slidable member flexes thedistal section in a manner that steers the delivery device through bendsand bifurcations in the lumen of the respiratory system. In otherembodiments, the steering mechanism comprises a flexible support elementand a flexible control element attached to the flexible support elementsuch that tension applied to the control element flexes the flexiblesupport element. Suitable steering mechanisms are set forth in U.S. Pat.No. 6,702,780 and U.S. Patent Application Publication No. US2003/0208101 A1, both of which are incorporated herein by reference.

FIG. 1E is an isometric view of a delivery device 820 in accordance withanother embodiment of the invention. The delivery device 820 can be aneedle or other type of introducer for percutaneously implanting themarker 40 into the lung of the patient trans-thoracically. The deliverydevice 820 includes a handle 822, a slider 824 received in the handle822, and an actuator 826 attached to the slider 824. The delivery device820 further includes a cannula 828 attached to the slider 824 and astylet 829 fixedly attached to the handle 822. In operation, the cannula828 and stylet 829 are percutaneously inserted into the patient. Whenthe marker 40 is at a desired location relative to the target, theactuator 826 is drawn proximately to move the slider 824 proximallywithin the handle 822. This motion withdraws the cannula 828 over thestylet 829 to release the marker 40 in the patient. The delivery device820 and several other embodiments of delivery devices for percutaneousimplantation of the markers are described in U.S. Patent Application No.60/590,521 and U.S. Pat. No. 7,247,160, both of which are incorporatedherein by reference in their entirety.

Referring now to FIGS. 3A-3D, the distal end 216 of the deliverycatheter 212 releasably retains the marker 220. As shown in FIG. 3A, anoutside diameter of the marker 220 can be approximately equal to thediameter of the channel 211. Alternatively, as shown in FIG. 3C, asleeve 406 can be placed at a distal end 216 of the delivery catheter412. An inside diameter of the sleeve 406 can be approximately equal tothe outside diameter of the marker 220 and configured to releasablyretain the marker 220. According to this embodiment, the channel 411 canhave an inside diameter smaller than the outside diameter of the marker220. The sleeve 406 may be made from a semi-rigid, rigid, or flexiblematerial different from the catheter 412, or may be made from the samematerial as the catheter 412.

Referring now to FIG. 3D, the distal end 516 of the delivery catheter512 releasably retains the marker 220 by expanding around the marker220. According to aspects of this embodiment, the inside diameter of thedelivery catheter 512 is less that the outside diameter of the marker220. The delivery catheter 512 is made from a sufficiently flexiblematerial to allow the delivery catheter 512 to expand around the marker220 and releasably retain the marker 220 prior to deployment.Alternatively, another method besides compression fit to hold the markerin place is to use a material for example, coconut oil that is solid atroom temperature and liquid at body temperature. Alternately, thematerial could be liquid soluble, such as sucrose or NaCl; exposure tothe lumen would detach the marker.

Referring now to FIG. 4, a cut away schematic view of the distal end ofa delivery catheter in accordance with an embodiment of the disclosureis shown. A retention sleeve 606 is placed at the distal end 616 of thedelivery catheter 612. An inside diameter of the sleeve 606 can beapproximately equal to the outside diameter of the marker. Thedeployment wire or push wire 618 includes an engagement member 620 and adeployment member 622. The engagement member 620 is positioned at adistal end of the push wire and is configured as a ball end in FIG. 4.Alternatively, the engagement member 620 may be a wedge, a plate orother geometric shape as appropriate. The deployment member 622 ispositioned co-axially at a predetermined distance away from the distalend of the push wire. As will be understood by one skilled in the art,the deployment member 622 may be a tapered wedge as shown or may be anyother geometric shape.

FIG. 5 is a cross-sectional view of an exemplary healthy respiratorysystem 110 having markers 220 a-c positioned therein. The respiratorysystem 110 resides within a thorax 16 which occupies a space defined bya chest wall 12 and a diaphragm 13. The respiratory system 10 includestrachea 16; left mainstem bronchus 20 and right mainstem bronchus 22(primary, or first generation); lobar bronchial branches 24, 26, 28, 30,32, 38 and 40 (second generation), and segmental branches 34 and 36(third generation). The respiratory system 10 further includes left lunglobes 42 and 44 and right lung lobes 46, 48 and 50. Each bronchialbranch and sub-branch communicates with a different portion of a lunglobe, either the entire lung lobe or a portion thereof. As used herein,the term “passageway” is meant to denote either a bronchi or bronchioli,and typically means a bronchial branch of any generation.

As shown in FIG. 5, three transponders 220 a-c are positioned in therespiratory system 110 of a patient in the proximity of a tumor orlesion 100. The transponders 220 a-c are used to localize a patienttarget treatment isocenter relative to a linear accelerator machineisocenter as described further herein. As a process step duringradiation therapy treatment planning, a patient undergoes a CT scanwhereby the X, Y, and Z positions of the radiographic centers for allthree transponders 220 a-c as well as the X, Y, and Z position for thetreatment target isocenter are identified. To localize a patienttreatment target isocenter relative to the linear accelerator treatmenttarget isocenter both prior to and during radiation therapy delivery,the three transponder positions that are positioned in the lung arelocalized electromagnetically and then used to calculate the position ofthe treatment target isocenter position and rotational offsets.

The markers 220 a-c are placed in the respiratory system 110 by thebronchoscopic catheter assembly 200 as described further herein. Themarkers 220 a-c are preferably a small alternating magnetic transponder.The transponders can each have a unique frequency relative to each otherto allow for time and frequency multiplexing. The transponders canaccordingly include a core, a coil wound around the core, and acapacitor electrically coupled to the coil. The bronchoscopic catheterassembly 200 can deploy one or more transponders, and as such is notlimited to having three transponders as illustrated. The transpondersare localized using a source, sensor array, receiver, and localizationalgorithm as described further herein.

In operation, the three transponders may be used to localize a treatmenttarget isocenter relative to a linear accelerator radiation therapytreatment isocenter. The treatment target localization may include bothtranslational offset (X, Y, and Z directions) and a rotational offset(pitch, yaw, and roll) relative to a linear accelerator coordinatereference frame.

C. CATHETER TIP CONFIGURED TO REDUCE PNEUMOTHORAX

According to aspects of the invention, a distal end of a catheter isconfigured to reduce pneumothorax. The marker 220 is pre-loaded into thedistal end 216 of the delivery catheter 212 such that a portion of themarker 220 extends beyond the distal end 216 of the delivery catheter212, thus providing a rounded leading end of the delivery catheter 212.Providing a rounded leading end of the distal end of the deliverycatheter 212 by pre-loading a cylindrical shaped marker, such as atransponder, reduces the puncture rate of the visceral pleura which canoccur during bronchoscopic implantation, and thus reduces the likelihoodof pneumothorax. Without being bound by theory, pre-loading thecylindrical shaped marker provides a rounded end shape to the deliverycatheter 212; the rounded end shape keeps the delivery catheter 212centered in the passageway. The rounded leading end also maximizes thesurface area of tissue (e.g. visceral pleura) that the distal end of thecatheter contacts. The catheter distal end is thus less likely to cutthrough tissue since it maximizes tissue surface area contact byincorporating a smooth rounded tip that does not include any edges thatcould concentrate force facilitate tissue perforation.

D. RADIATION THERAPY SYSTEMS WITH REAL-TIME TRACKING SYSTEMS

FIGS. 6 and 7 illustrate various aspects of a radiation therapy system 1for applying guided radiation therapy to a target 2 (e.g., a tumor)within a lung or other part of a patient 6. The radiation therapy system1 has a localization system 10 and a radiation delivery device 20. Thelocalization system 10 is a tracking unit that locates and tracks theactual position of the target 2 in real time during treatment planning,patient setup, and/or while applying ionizing radiation to the targetfrom the radiation delivery device. Moreover, the localization system 10continuously tracks the target and provides objective data (e.g.,three-dimensional coordinates in an absolute reference frame) to amemory device, user interface, linear accelerator, and/or other device.The system 1 is described below in the context of guided radiationtherapy for treating a tumor or other target in the lung of the patient,but the system can be used for tracking and monitoring other targetswithin the patient for other therapeutic and/or diagnostic purposes.

The radiation delivery source of the illustrated embodiment is anionizing radiation device 20 (i.e., a linear accelerator). Suitablelinear accelerators are manufactured by Varian Medical Systems, Inc. ofPalo Alto, Calif.; Siemens Medical Systems, Inc. of Iselin, N.J.; ElektaInstruments, Inc. of Iselin, N.J.; or Mitsubishi Denki Kabushik Kaishaof Japan. Such linear accelerators can deliver conventional single ormulti-field radiation therapy, 3D conformal radiation therapy (3D CRT),IMRT, stereotactic radiotherapy, and tomo therapy. The radiationdelivery device 20 can deliver a gated, contoured, or shaped beam 21 ofionizing radiation from a movable gantry 22 to an area or volume at aknown location in an external, absolute reference frame relative to theradiation delivery device 20. The point or volume to which the ionizingradiation beam 21 is directed is referred to as the machine isocenter.

The tracking system includes the localization system 10 and one or moremarkers 220. The localization system 10 determines the actual locationof the markers 220 in a three-dimensional reference frame, and themarkers 220 are typically within the patient 6. In the embodimentillustrated in FIGS. 6 and 7, more specifically, three markersidentified individually as markers 220 a-c are implanted in the lung ofthe patient 6 at locations in or near the target 2. In otherapplications, a single marker, two markers, or more than three markerscan be used depending upon the particular application. The markers 220are desirably placed relative to the target 2 such that the markers 220are at least substantially fixed relative to the target 2 (e.g., themarkers move at least in direct proportion to the movement of thetarget). As discussed above, the relative positions between the markers220 and the relative positions between a target isocenter T of thetarget 2 and the markers 220 can be determined with respect to anexternal reference frame defined by a CT scanner or other type ofimaging system during a treatment planning stage before the patient isplaced on the table. In the particular embodiment of the system 1illustrated in FIGS. 6 and 7, the localization system 10 tracks thethree-dimensional coordinates of the markers 220 in real time relativeto an absolute external reference frame during the patient setup processand while irradiating the patient to mitigate collateral effects onadjacent healthy tissue and to ensure that the desired dosage is appliedto the target.

E. GENERAL ASPECTS OF MARKERS AND LOCALIZATION SYSTEMS

FIG. 8 is a schematic view illustrating the operation of an embodimentof the localization system 10 and markers 220 a-c for treating a tumoror other target in the lung of the patient. The localization system 10and the markers 220 a-c are used to determine the location of the target2 (FIGS. 6 and 7) before, during, and after radiation sessions. Morespecifically, the localization system 10 determines the locations of themarkers 220 a-c and provides objective target position data to a memory,user interface, linear accelerator, and/or other device in real timeduring setup, treatment, deployment, simulation, surgery, and/or othermedical procedures.

In one embodiment of the localization system, real time means thatindicia of objective coordinates are provided to a user interface at (a)a sufficiently high refresh rate (i.e., frequency) such that pauses inthe data are not humanly discernable and (b) a sufficiently low latencyto be at least substantially contemporaneous with the measurement of thelocation signal. In other embodiments, real time is defined by higherfrequency ranges and lower latency ranges for providing the objectivedata to a radiation delivery device, or in still other embodiments realtime is defined as providing objective data responsive to the locationof the markers (e.g., at a frequency that adequately tracks the locationof the target in real time and/or a latency that is substantiallycontemporaneous with obtaining position data of the markers).

1. Localization Systems

The localization system 10 includes an excitation source 60 (e.g., apulsed magnetic field generator), a sensor assembly 70, and a controller80 coupled to both the excitation source 60 and the sensor assembly 70.The excitation source 60 generates an excitation energy to energize atleast one of the markers 220 a-c in the patient 6 (FIG. 6). Theembodiment of the excitation source 60 shown in FIG. 8 produces a pulsedmagnetic field at different frequencies. For example, the excitationsource 60 can frequency multiplex the magnetic field at a firstfrequency E1 to energize the first marker 220 a, a second frequency E2to energize the second marker 220 b, and a third frequency E3 toenergize the third marker 220 c. In response to the excitation energy,the markers 220 a-c generate location signals L1-3 at unique responsefrequencies. More specifically, the first marker 220 a generates a firstlocation signal L1 at a first frequency in response to the excitationenergy at the first frequency E1, the second marker 220 b generates asecond location signal L2 at a second frequency in response to theexcitation energy at the second frequency E2, and the third marker 220 cgenerates a third location signal L3 at a third frequency in response tothe excitation energy at the third frequency E3. In an alternativeembodiment with two markers, the excitation source generates themagnetic field at frequencies E1 and E2, and the markers 220 a-bgenerate location signals L1 and L2, respectively.

The sensor assembly 70 can include a plurality of coils to sense thelocation signals L1-3 from the markers 220 a-c. The sensor assembly 70can be a flat panel having a plurality of coils that are at leastsubstantially coplanar relative to each other. In other embodiments, thesensor assembly 70 may be a non-planar array of coils.

The controller 80 includes hardware, software, or othercomputer-operable media containing instructions that operate theexcitation source 60 to multiplex the excitation energy at the differentfrequencies E1-3. For example, the controller 80 causes the excitationsource 60 to generate the excitation energy at the first frequency E1for a first excitation period, and then the controller 80 causes theexcitation source 60 to terminate the excitation energy at the firstfrequency E1 for a first sensing phase during which the sensor assembly70 senses the first location signal L1 from the first marker 220 awithout the presence of the excitation energy at the first frequency E1.The controller 80 then causes the excitation source 60 to: (a) generatethe second excitation energy at the second frequency E2 for a secondexcitation period; and (b) terminate the excitation energy at the secondfrequency E2 for a second sensing phase during which the sensor assembly70 senses the second location signal L2 from the second marker 220 bwithout the presence of the second excitation energy at the secondfrequency E2. The controller 80 then repeats this operation with thethird excitation energy at the third frequency E3 such that the thirdmarker 220 c transmits the third location signal L3 to the sensorassembly 70 during a third sensing phase. As such, the excitation source60 wirelessly transmits the excitation energy in the form of pulsedmagnetic fields at the resonant frequencies of the markers 220 a-cduring excitation periods, and the markers 220 a-c wirelessly transmitthe location signals L1-3 to the sensor assembly 70 during sensingphases. It will be appreciated that the excitation and sensing phasescan be repeated to permit averaging of the sensed signals to reducenoise.

The computer-operable media in the controller 80, or in a separatesignal processor, or other computer also includes instructions todetermine the absolute positions of each of the markers 220 a-c in athree-dimensional reference frame. Based on signals provided by thesensor assembly 70 that correspond to the magnitude of each of thelocation signals L1-3, the controller 80 and/or a separate signalprocessor calculates the absolute coordinates of each of the markers 220a-c in the three-dimensional reference frame. The absolute coordinatesof the markers 220 a-c are objective data that can be used to calculatethe coordinates of the target in the reference frame. When multiplemarkers are used, the rotation of the target can also be calculated.

2. Real-Time Tracking

The localization system 10 and at least one marker 220 enable real-timetracking of the target 2 relative to the machine isocenter or anotherexternal reference frame outside of the patient during treatmentplanning, setup, radiation sessions, and at other times of the radiationtherapy process. In many embodiments, real-time tracking meanscollecting position data of the markers, determining the locations ofthe markers in an external reference frame, and providing an objectiveoutput in the external reference frame that is responsive to thelocation of the markers. The objective output is provided at a frequencythat adequately tracks the target in real time and/or a latency that isat least substantially contemporaneous with collecting the position data(e.g., within a generally concurrent period of time).

For example, several embodiments of real-time tracking are defined asdetermining the locations of the markers and calculating the location ofthe target relative to the machine isocenter at (a) a sufficiently highfrequency so that pauses in representations of the target location at auser interface do not interrupt the procedure or are readily discernableby a human, and (b) a sufficiently low latency to be at leastsubstantially contemporaneous with the measurement of the locationsignals from the markers. Alternatively, real time means that thelocalization system 10 calculates the absolute position of eachindividual marker 220 and/or the location of the target at a periodicityof 1 ms to 5 seconds, or in many applications at a periodicity ofapproximately 10-100 ms, or in some specific applications at aperiodicity of approximately 20-50 ms. In applications for userinterfaces, for example, the periodicity can be 12.5 ms (i.e., afrequency of 80 Hz), 16.667 ms (60 Hz), 20 ms (50 Hz), and/or 50 ms (20Hz).

Alternatively, real-time tracking can further mean that the localizationsystem 10 provides the absolute locations of the markers 220 and/or thetarget 2 to a memory device, user interface, linear accelerator, orother device within a latency of 10 ms to 5 seconds from the time thelocalization signals were transmitted from the markers 220. In morespecific applications, the localization system generally provides thelocations of the markers 220 and/or target 2 within a latency of about20-50 ms. The localization system 10 accordingly provides real-timetracking to monitor the position of the markers 220 and/or the target 2with respect to an external reference frame in a manner that is expectedto enhance the efficacy of radiation therapy because higher radiationdoses can be applied to the target and collateral effects to healthytissue can be mitigated.

The system described herein uses one or more markers to serve asregistration points to characterize target location, rotation, andmotion. In accordance with aspects of the invention, the markers have asubstantially fixed relationship with the target. If the markers did nothave a substantially fixed relationship with the target, another type oftracking error would be incurred. This generally requires the markers tobe fixed or positioned sufficiently close to the target in order thattracking errors be within clinically meaningful limits; thus, themarkers may be placed in tissue or bone that exhibits representativemotion of the target. For example, with respect to the lung, a devicethat is representative of the target's motion would include a markerretained in bronchi of a patient.

According to aspects of the present invention, the marker motion is asurrogate for the motion of the target. Accordingly, the marker isplaced such that it moves in direct correlation to the target beingtracked. Depending on the target being tracked, the direct correlationrelationship between the target and the marker will vary. For example,with respect to soft tissue that moves substantially in response to therespirations of the patient, such as the lung, the marker may be placedin a bronchi to provide surrogate motion in direct correlation withtarget motion.

FIG. 9 is a flow diagram illustrating several aspects and uses ofreal-time tracking to monitor the location and the status of the target.In this embodiment, an integrated method 90 for radiation therapyincludes a radiation planning procedure 91 that determines the plan forapplying the radiation to the patient over a number of radiationfractions. The radiation planning procedure 91 typically includes animaging stage in which images of a tumor or other types of targets areobtained using X-rays, CT, MR, or ultrasound imaging. The images areanalyzed by a person to measure the relative distances between themarkers and the relative position between the target and the markers.FIG. 10A, for example, is a representation of a CT image showing across-section of the patient 6, the target 2, and a marker 220.Referring to FIG. 10B, the coordinates (x0, y0, z0) of the marker 220 ina reference frame RCT of the CT scanner can be determined by anoperator. The coordinates of the tumor can be determined in a similarmanner to ascertain the offset between the marker and the target.Alternatively, the coordinates of a radiographic fiducial 30 in areference frame RCT of the CT scanner can be determined by an operator.

The localization system 10 and the markers 220 enable an automatedpatient setup process for delivering the radiation. After developing atreatment plan, the method 90 includes a setup procedure 92 in which thepatient is positioned on a movable support table so that the target andmarkers are generally adjacent to the sensor assembly. As describedabove, the excitation source is activated to energize the markers, andthe sensors measure the strength of the signals from the markers. Thecomputer controller then (a) calculates objective values of thelocations of the markers and the target relative to the machineisocenter, and (b) determines an objective offset value between theposition of the target and the machine isocenter. Referring to FIG. 11,for example, the objective offset values can be provided to a userinterface that displays the vertical, lateral, and longitudinal offsetsof the target relative to the machine isocenter. A user interface may,additionally or instead, display target rotation.

One aspect of several embodiments of the localization system 10 is thatthe objective values are provided to the user interface or other deviceby processing the position data from the field sensor 70 in thecontroller 80 or other computer without human interpretation of the datareceived by the sensor assembly 70. If the offset value is outside of anacceptable range, the computer automatically activates the controlsystem of the support table to move the tabletop relative to the machineisocenter until the target isocenter is coincident with the machineisocenter. The computer controller generally provides the objectiveoutput data of the offset to the table control system in real time asdefined above. For example, because the output is provided to theradiation delivery device, it can be at a high rate (1-20 ms) and a lowlatency (10-20 ms). If the output data is provided to a user interfacein addition to or in lieu of the table controller, it can be at arelatively lower rate (20-50 ms) and higher latency (50-200 ms).

In one embodiment, the computer controller also determines the positionand orientation of the markers relative to the position and orientationof simulated markers. The locations of the simulated markers areselected so that the target will be at the machine isocenter when thereal markers are at the selected locations for the simulated markers. Ifthe markers are not properly aligned and oriented with the simulatedmarkers, the support table is adjusted as needed for proper markeralignment. This marker alignment properly positions the target along sixdimensions, namely X, Y, Z, pitch, yaw, and roll. Accordingly, thepatient is automatically positioned in the correct position and rotationrelative to the machine isocenter for precise delivery of radiationtherapy to the target.

Referring back to FIG. 9, the method 90 further includes a radiationsession 93. FIG. 12 shows a further aspect of an automated process inwhich the localization system 10 tracks the target during the radiationsession 93 and controls the radiation delivery source 20 according tothe offset between the target and the machine isocenter. For example, ifthe position of the target is outside of a permitted degree or range ofdisplacement from the machine isocenter, the localization system 10sends a signal to interrupt the delivery of the radiation or preventinitial activation of the beam. In another embodiment, the localizationsystem 10 sends signals to automatically reposition a table 27 and thepatient 6 (as a unit) so that the target isocenter remains within adesired range of the machine isocenter during the radiation session 93even if the target moves. In still another embodiment, the localizationsystem 10 sends signals to activate the radiation only when the targetis within a desired range of the machine isocenter (e.g., gatedtherapy). In some embodiments, the localization system enables dynamicadjustment of the table 27 and/or the beam 21 in real time whileirradiating the patient. Dynamic adjustment of the table 27 ensures thatthe radiation is accurately delivered to the target without requiring alarge margin around the target.

The localization system 10 provides the objective data of the offsetand/or rotation to the linear accelerator and/or the patient supporttable in real time as defined above. For example, as explained abovewith respect to automatically positioning the patent support tableduring the setup procedure 92, the localization system generallyprovides the objective output to the radiation delivery device at leastsubstantially contemporaneously with obtaining the position data of themarkers and/or at a sufficient frequency to track the target in realtime. The objective output, for example, can be provided at a shortperiodicity (1-20 ms) and a low latency (10-20 ms) such that signals forcontrolling the beam 21 can be sent to the radiation delivery source 20in the same time periods during a radiation session. In another exampleof real-time tracking, the objective output is provided a plurality oftimes during an “on-beam” period (e.g., 2, 5, 10, or more times whilethe beam is on). In the case of terminating or activating the radiationbeam, or adjusting the leaves of a beam collimator, it is generallydesirable to maximize the refresh rate and minimize the latency. In someembodiments, therefore, the localization system may provide theobjective output data of the target location and/or the marker locationsat a periodicity of 10 ms or less and a latency of 10 ms or less. Themethod 90 may further include a verification procedure 94 in whichobjective output data from the radiation session 93 is compared to thestatus of the parameters of the radiation beam.

The method 90 can further include a first decision (Block 95) in whichthe data from the verification procedure 94 is analyzed to determinewhether the treatment is complete. If the treatment is not complete, themethod 90 further includes a second decision (Block 96) in which theresults of the verification procedure are analyzed to determine whetherthe treatment plan should be revised to compensate for changes in thetarget. If revisions are necessary, the method can proceed withrepeating the planning procedure 91. On the other hand, if the treatmentplan is providing adequate results, the method 90 can proceed byrepeating the setup procedure 92, radiation session 93, and verificationprocedure 94 in a subsequent fraction of the radiation therapy.

The localization system 10 provides several features, eitherindividually or in combination with each other, that enhance the abilityto accurately deliver high doses of radiation to targets within tightmargins. For example, many embodiments of the localization system useleadless markers that are substantially fixed with respect to thetarget. The markers accordingly move either directly with the target orin a relationship proportional to the movement of the target. Moreover,many aspects of the localization system 10 use a non-ionizing energy totrack the leadless markers in an external, absolute reference frame in amanner that provides objective output. In general, the objective outputis determined in a computer system without having a human interpret data(e.g., images) while the localization system 10 tracks the target andprovides the objective output. This significantly reduces the latencybetween the time when the position of the marker is sensed and theobjective output is provided to a device or a user. For example, thisenables an objective output responsive to the location of the target tobe provided at least substantially contemporaneously with collecting theposition data of the marker. The system also effectively eliminatesinter-user variability associated with subjective interpretation of data(e.g., images).

F. EMBODIMENTS OF ANCHORABLE MARKERS

Referring now to FIG. 13, an anchorable marker assembly includes amarker 220 having a casing, a magnetic transponder (e.g., a resonatingcircuit) at least partially encased in the casing, a shell assembly 702and an anchor assembly. The anchor assembly includes an anchor disk 710(shown in later figures) and fasteners 708 such as shape memory legs,extending from the anchor disk 712.

Referring now to FIGS. 14A and 14B, an anchorable marker assembly 700may include a marker 220, a shell assembly 702 around the marker 220, ananchor disk 710 adjacent to a proximal end of the marker 220, and aplurality of fasteners or legs 708 attaching to the anchor disk 710 andextending proximally. The legs 708 may further include an end stop 704at a far proximal end. The end stop 704 may further include a barb 706extending at an angle outward. As further shown in the cutaway view ofFIG. 14B, the anchor disk 710 may be held in a fixed position in theshell assembly 702 by anchor sleeve 712 and adhesive 714.

Referring now to FIG. 15, an exploded view of the anchorable assembly700 of FIGS. 14A and 14B is shown. According to this embodiment, theshell assembly 702, the anchor sleeve 712, the legs 708 and the anchordisk may interlock 716 during assembly. This mechanical interlockbetween the shell components and the Nitinol® leg stability featureprovides a high intra-component mechanical strength. According toalternative embodiments, the legs may be mated into grooves in theanchor disk, providing further positive mechanical interlock. Otherinterlock configurations may be used within the scope of thisdisclosure, including but not limited to: star shaped and inverted starshape anchor disk; direct leg-to-shell interlock; single piece multi-legcage interlocks and the like.

Referring now to FIGS. 16A, 16B and 16C a delivery catheter with apre-loaded anchorable marker assembly, including the loaded catheterassembly of FIG. 16A, is shown. FIG. 16B shows a cutaway view of theloaded catheter and FIG. 16C shows a deployed view of the marker afterit has been deployed from the catheter. As illustrated in thisembodiment, the internal shell-catheter may overlap for articulation inuse. The exemplary configuration allows the distal end of the catheterto dock with the marker and articulation between the marker and thecatheter provides axial flexibility and a reduction in forces whenpassing through tortuous or curved pathways. Furthermore, an internalshell-catheter overlap may cover a sharp edge on the deliver catheter toavoid airway wall injury.

Referring now to FIGS. 17A and 17B, a preloaded delivery catheter 1700and an anchorable marker assembly deployed from the delivery catheterare shown. According to this embodiment, the distal end of the push wireincludes an engagement member 720. In this embodiment, the engagementmember is configured as a retention bulb shaped to retain the fasteners708 when the anchorable marker assembly is retained in the deliverycatheter prior to deployment. As will be appreciated by one skilled inthe art, the engagement member may take any geometrical shape to nestwithin and retain the fasteners when the anchorable marker assembly isretained in the delivery catheter prior to deployment.

FIG. 18A shows a preloaded delivery catheter 1800 and FIG. 18B shows ananchorable marker assembly after being deployed from the deliverycatheter. According to this embodiment, the distal end of the push wireincludes an engagement member 720. According to further aspects, abreakaway means is included between a first part 702 a of the shellassembly 702 and a second part 702 b of the shell assembly 702. Inoperation, the marker is deployed when the deployment force exceeds abreakaway force. The breakaway means may include a weakened portion ofthe shell assembly 702 in the form of a perforation, crease, thinnedsection or the like. According to alternative embodiments, a localdeformation or crumple zone may exist to accommodate permanentdeformation in the shell. The deformation zone can be designed to allowdeformation in a specific region (e.g. between the first part 702 a ofthe shell assembly 702 and the second part 702 b of the shell assembly)without damage to function and performance of the shell assembly 702.

Referring now to FIGS. 19A and 19B, a preloaded delivery catheter 1900and an anchorable marker assembly deployed from the delivery catheter isshown. According to this embodiment, the distal end of the push wireincludes an engagement member 720. In this embodiment, the shellassembly 702 extends proximally over the anchor disk 710 and over someportion of the fasteners 704 to form a skirt at the proximal end of themarker. According to aspects of this embodiment, the overlap at themarker/catheter interface ensures that the marker and the catheterremain engaged during handling of preloaded catheters and while passingthe preloaded catheter through small bend radii. According to stillfurther aspects, the overlap provides a flexibility at themarker/catheter interface and can further include an articulated sectionat the marker/catheter interface.

FIG. 20A shows a preloaded delivery catheter 2000 and Figure B shows ananchorable marker assembly deployed from the delivery catheter.According to this embodiment, the distal end of the push wire includesan engagement member 720. In this embodiment, the engagement member isconfigured as an interlock having recesses shaped to engage thefasteners 708 when the anchorable marker assembly is retained in thedelivery catheter prior to deployment. According to aspects of thisembodiment, the interlocking engagement member provides a positivemechanical interlock to retain the marker in the preloaded catheter.

FIG. 21A shows a preloaded delivery catheter 2100 and FIG. 21B shows ananchorable marker assembly deployed from the delivery catheter.According to this embodiment, the distal end of the push wire includesan engagement member 720. In this embodiment, the engagement member isconfigured as a further interlock shape configured to include slots toreceive the fasteners 708 when the anchorable marker assembly isretained in the delivery catheter prior to deployment. In thisembodiment, the engagement member is configured as an interlock shapedto engage the fasteners 708 when the anchorable marker assembly isretained in the delivery catheter prior to deployment. According toaspects of this embodiment, the interlocking engagement member providesmore positive mechanical interlock to retain the maker in the preloadedcatheter.

FIG. 22A shows a preloaded delivery catheter 2200 and FIG. 22B shows ananchorable marker assembly deployed from the delivery catheter.According to this embodiment, the distal end of the push wire includesan engagement member 720. In this embodiment, the engagement member isconfigured as a retention bulb which includes a collet for receiving anelement of the fastener assembly shown in this embodiment to include alarger diameter head at a distal end for engaging the engagement member.The engagement member is configured to receive the element 707 a of thefastener assembly in the collet to provide a positive mechanicalinterlock to retain the anchorable marker assembly in the deliverycatheter prior to deployment.

FIG. 23A shows a preloaded delivery catheter 2300 and FIG. 23B shows ananchorable marker assembly deployed from the delivery catheter. Inalternative embodiments, the marker is not preloaded in the deliverycatheter. According to this embodiment, the distal end of the push wireincludes an engagement member 720. In this embodiment, the engagementmember is configured as a retention rod which includes a collet forreceiving an element 707 b of the fastener assembly. The engagementmember is configured to receive the retained member 707 b in the colletto provide a positive mechanical interlock to retain the anchorablemarker assembly in the delivery catheter prior to deployment.

Referring now to FIGS. 24A-24D, cross-sectional and end views of theanchorable assemblies illustrating various loading and unloadingconfigurations are shown. For example in FIG. 24A, anchorable markerassemblies are shown loaded in the deliver catheter in series. Analternate loading configuration shown in FIG. 24B shows the anchorableassemblies loaded in parallel in a delivery catheter. One skilled in theart will understand that a variety of single and multiple loadingconfigurations are within the disclosure of this application. Referringnow to FIG. 24C, an alternative unloading pattern is illustrated whereinthe markers are directed to exit the delivery catheter out a side portalof the catheter. According to the embodiment shown in FIG. 24D, multipleindividual anchorable marker assemblies are loaded in an untetheredmanner, separated by a dimple on the interior surface of the deliverycatheter. As will be understood by one skilled in the art, separationmeans may include a mechanical plug, ridge, bladder or other separationdevice, or may include a spacer of fluid, paste, gel or the like.Referring now to FIG. 26, multiple anchorable marker assemblies mayalternatively be deployed from an interconnected configuration whereinthe anti-migration element on a first marker engages with a retainingelement on a second marker.

Referring now to FIGS. 25A-25D, various positive stops are illustratedwhich provide controlled deployment stroke upon implementation.Referring to FIG. 25A, a dimple at a distal end of the delivery cathetermay engage with a collar portion of the push wire to provide a firststop for preventing the user from over-deploying. Also shown in FIG. 25Ais a protrusion extending from an interior of the catheter configured toengage the collar portion of the push wire and provide a second stopconfigured to prevent over retraction of the push wire. Referring toFIG. 25B, two stops may be provided, however in this embodiment, bothengage with a common protrusion shown on an interior of the catheter.According to this embodiment, a first stop prevents the user fromretracting the push wire beyond a predetermined distance and a secondstop prevents the user from over inserting the push wire beyond apredetermined distance. Referring to FIGS. 25C and 25D, alternativedeployment stop configurations are shown. It is recognized by thoseskilled in the art that alternative stops beyond the representativestops shown in FIGS. 25A-25D may be included and still fall within thescope of the disclosure. Furthermore, in operation, the distal end stopcan provide implant placement accuracy to less than 5 mm, by controllingthe stroke required to deploy the implant from the retention sleeve.Additionally, the distal end stop can limit ball protrusion from theretention sleeve; hold the deployment wire centered with respect to theretention sleeve during loading; prevent the legs from becomingentrapped behind disk after deployment; and minimize the likelihood ofimplant legs catching on ball during retraction.

According to further aspects of the disclosure, the casing is abiocompatible barrier, which can be made from plastics, ceramics, glassor other suitable materials, and the casing is configured to beimplanted in the patient. The casing can be a generally cylindricalcapsule that is sized to fit within a catheter for bronchoscopicimplantation. For example, the casing can have a diameter ofapproximately 2 mm or less. According to aspects of the invention, thecasing can have a slightly larger diameter than the inside diameter ofthe delivery catheter to retain the casing in the catheter duringplacement.

According to still further aspects of the disclosure, the magnetictransponder can include a resonating circuit that produces a wirelesslytransmitted signal in response to a wirelessly transmitted excitationfield. In one embodiment, the magnetic transponder comprises a coildefined by a plurality of windings around a conductor. Many embodimentsof the magnetic transponder also include a capacitor coupled to thecoil. The coil can resonate at a resonant frequency solely using theparasitic capacitance of the windings without having a capacitor, or theresonant frequency can be produced using the combination of the coil andthe capacitor. The coil accordingly defines a signal transmitter thatgenerates an alternating magnetic field at the selected resonantfrequency in response to the excitation energy either by itself or incombination with the capacitor. The coil generally has 800-2000 turns,and the windings are preferably wound in a tightly layered coil.

The magnetic transponder can further include a core composed of amaterial having a suitable magnetic permeability. For example, the corecan be a ferromagnetic element composed of ferrite or another material.Suitable embodiments of magnetic transponders are disclosed in U.S.patent application Ser. Nos. 10/334,698 and 10/746,888, which areincorporated herein by reference in their entirety.

Several of the embodiments shown in Figures illustrate the anchor may beembedded in the marker or the anchor may be contained in the deliverycatheter such that the anchor is deployed adjacent to the marker toprevent the marker from migrating. Alternatively, the fastener can be aseparate component attached to and/or embedded in the casing. Accordingto aspects of the invention, a fastener or anchor protruding from themarker casing wherein the fastener can be an integral extension of thecasing. When the fastener is a separate component, it can be made from asuitable biocompatible material, such as metals, metal alloys, polymers,PEEK, glass, epoxy adhesive, silicone adhesive and/or other syntheticmaterials. An example of one such material is spring steel, althoughother “memory” metal alloys such as Nitinol® may be suitable. Accordingto further aspects of the invention, an outer shape can employ shapememory alloy features that “grow” into bronchiole as internal bodytemperature expands the alloy.

Another embodiment of a marker comprises a marker section configured tobe localized and an anchor attached to the marker section. The anchorcomprises an expandable member that moves between a stored positionhaving a first size and a deployed position having a second size greaterthan the first size. The anchor, for example, can be a stent, anumbrella-like expandable member, or an expandable cylindrical section asshown in the Figures.

Alternative anti-migration devices and methods that prevent thetransponder from moving from the implantation position to a moreproximal position relative to the trachea include positioning theanti-migration device either behind the transponder in the catheter ordelivered through the catheter after transponder deployment (e.g.,glue). Additionally, glue or other chemical material may be deliveredthrough the delivery catheter to function as an anti-migration device.The glue may be pre-packaged within the catheter or injected through thecatheter after implantation. Alternatively, a hydroscopic material thatexpands due to contact with bodily fluids may act as an anti-migrationdevice, for example, a hydrogel, a hygroscopic material, and/or asponge. According to yet another embodiment, suture material may bepushed out of the catheter and compacted to plug the vessel and serve asan anti-migration device.

Alternative design of the anti-migration devices such as: legs withoutbarbs; barbs contained on some of the legs but not others; a pluralityof legs with unequal leg length; a braided stability feature; a coilstability feature, long length leg stability feature design; coils;interconnected legs and/or spring loaded stability features are allwithin the scope of the disclosure as will be understood by one skilledin the art.

G. ALTERNATIVE EMBODIMENTS OF ANCHORABLE MARKERS

According to alternative aspects of the disclosure, the design allowsfor the ability to retrieve the implant from airway after implantation.During a bronchoscopic procedure, a commercially available accessorytool (eg. biopsy forceps, snare, retrieval basket) is used to grasp asingle leg or multiple legs of the stability feature and retrieve fromthe airway.

Further in accordance with the disclosure, bronchoscopic implantation ofan implant in the airway has a lower risk of complication when comparedto a needle based percutaneous implantation in the airway, and thereforebronchscopic placement is the preferred method.

An alternative embodiment provides for central airway application,wherein the implant is implanted in a larger diameter airway. Designchanges to the implant are expected to focus on a scale-up of thestability feature, designed for positional stability in larger airways,and potentially, allow for retrieval if needed. Alternatively theimplant may be implanted in the airway wall; in which case, modificationto the stability feature would focus on a scale-down of the stabilityfeature.

According to still further aspects of the disclosure, the catheterdelivery device can be include a modified stability feature forimplantation in organs, vessels and tissues other than lung airwayspercutaneously, laparoscopically, natural orifice transluminalendoscopiclly. Alternatively, the catheter deliver device can include animplant without a stability feature preloaded in a delivery catheter,for example for Catheterization of the Subarachnoid Space and placementin the brain. According to still further embodiments, the stabilityfeature (multi-legged design) could be used to provide positionalstability for other devices such as gold seeds, coils, or other fiducialmarkers implanted in airways in the lung. According to still furtherembodiments, generic delivery catheter could be used to deliver otherdevices such as a transponder, gold seeds, coils, or other fiducialmarkers in the lung. Further in accordance with the disclosure, adelivery catheter design where more than one implant is preloaded in thedistal end of the delivery catheter. Such a design would further improveease of use, and eliminate the workflow due to exchange of the singleuse catheter after deployment, and introduction of the next deliverycatheter.

In operation, once the distal end of the delivery catheter is positionedat the implantation site, the user withdraws the delivery catheterapproximately 1-2 cm so as to provide a space for the anchoredtransponder to be deployed in. This accounts for the travel of theanchored transponder upon handle actuation/deployment, supports accurateplacement of the anchored transponder and prevents bronchial injury orserious injury such as pneumothorax. Actuation/deployment can also byaccomplished by simultaneous actuation of the handle and withdrawal ofthe catheter, or actuation/deployment without a space for the anchoredtransponder to be deployed in.

H. EXEMPLARY IMPLANTATION PROCEDURE

In operation, a bronchoscope is inserted into the nose or mouth of apatient past the vocal chords and into the lungs by threading a distalend through the bronchi. At least one marker is pre-loaded at the distalend 216 of the delivery catheter 212. Once the bronchoscope ispositioned relative to the tumor or lesion, the delivery catheter 212 ispositioned in the working channel of the bronchoscope such that thedistal end 216 of the delivery catheter 212 is at or slightly beyond adistal end of the bronchoscope. Once the delivery catheter 212 is in thedesired position, the actuator is engaged, causing the push wire to moveaxially within the channel and deploy the marker. After at least onemarker is deployed, a second marker can be deployed; the catheter can berepositioned prior to deploying a second catheter; the catheter can beremoved and the bronchoscope can be removed or repositioned to deploy asecond marker; or the catheter can be repositioned to deploy a secondmarker. According to aspect of the invention, as the marker is deployedfrom the catheter, an anti-migration device integral to the marker orseparate from the marker can further be deployed to retain the marker ina desired position. According to this aspect, the anti-migration deviceanchors the marker to the anatomical anchoring site as further describedbelow.

Anchored transponders should be placed in small airways (approximately2-2.5 mm in diameter) that are within or near the tumor target to betreated. Preferred placement sites and the bronchoscopic path forreaching them should be determined before beginning the implantationprocedure. Anchored transponders may be placed during a standaloneprocedure or in conjunction with diagnostic bronchoscopy. Implantationshould be performed in an ambulatory procedure area or the operatingroom.

Each anchored transponder includes a small, passive, electricalcomponent encapsulated in biocompatible glass with an affixedmulti-legged anchoring feature. The legs of the anchoring feature areconstrained in the pre-loaded delivery catheter and becomeunconstrained, expanding outward, when the anchored transponder isdeployed in the airway. According to this embodiment, when completelyconstrained, the transponder diameter is approximately 2 mm; when thelegs are fully expanded, the diameter is approximately 5.5 mm.

Further in accordance with this embodiment, a separate delivery catheteris used to implant each anchored transponder into an airway within ornear the treatment target. Each single-use, delivery catheter ispre-loaded with an anchored transponder. According to one embodiment,the distal end of the delivery catheter is approximately 2 mm indiameter. The retention sleeve located at the distal tip of the deliverycatheter constrains the legs of the anchored transponder around thedeployment wire. According to aspects of one embodiment, the deliverycatheter is marked with graduations to assist in monitoring the lengthof the delivery catheter that has passed through the bronchoscope andinto the lung. In this embodiment, the graduations occur everycentimeter with a heavier mark every fifth centimeter.

Exemplary Implantation Techniques and Guidelines

Exemplary Guidelines to Provide Positional Stability of the AnchoredTransponder when Implanted in an Airway:

-   -   Place the anchored transponders in small airways (approximately        2-2.5 mm in diameter). If an anchored transponder is implanted        in a larger airway (diameter >2.5 mm), a greater volume of the        lung may be obstructed or the position of the anchored        transponder may not be stable.    -   For airways within or closely adjacent to a tumor, ensure that        the original airway diameter was small (approximately 2-2.5 mm).        Airways that have been invaded or compressed by a tumor may        expand as a result of therapy induced tumor shrinkage. If the        airway expands beyond 2.5 mm, a greater volume of the lung may        be obstructed or the positional stability of the implant may be        impacted.    -   If a central airway contains a stent, make sure that all        transponders are implanted beyond the distal end of the airway        stent.    -   If a sub segmental bronchus contains an airway stent, do not        implant an anchored transponder in that airway.    -   Do not implant more than one anchored transponder in the same        airway.    -   Avoid contact with already implanted anchored transponders when        implanting subsequent anchored transponders. Plan the order of        the implantations such that the anchored transponders in the        most distal locations are implanted first.

Guidelines to Ensure an Optimal Configuration of the AnchoredTransponders for Use with the Localization and Tracking System

-   -   The anchored transponders can be detectable by a localization        system in order to be used for localization and/or tracking. The        ability to detect the transponders is influences by their        configuration. The following guidelines are provided to help        achieve an optimal configuration.    -   The anchored transponders should be configured in a triangle and        distributed as evenly as possible around the target.    -   The distance between anchored transponders is between 1 cm and        7.5 cm.    -   Place the anchored transponders in a nonlinear configuration.

Exemplary Anchored Transponder Implantation Procedure

Preparation Before the Implantation Procedure

-   -   1. Determine when to perform the anchored transponder        implantation procedure relative to biopsy, chemotherapy, or        other events during the patient's course of treatment.    -   2. Confirm the patient's eligibility for implantation of the        anchored transponders and use of the localization and tracking        system.    -   3. Using a recent CT scan of the chest as a map of the        tracheobronchial tree, determine the intended implantation sites        according to the Implantation Site Recommendations. If possible,        note the specific airway path leading to each implantation site        and the approximate distance the delivery catheter will travel        into the airways to reach the intended site.    -   4. If a dedicated electromagnetic bronchoscopy or other guidance        system is used, enter the implantation sites into the system as        needed.    -   5. Per institutional and published guidelines consider        antibiotic prophylaxis for bronchoscopic procedures.

Preparation on the Day of Implantation

-   -   6. Prepare the patient as you would for a standard bronchoscopy        procedure.    -   7. Per the manufacturer's instructions, prepare any guidance        systems (fluoroscopy, electromagnetic guidance, ultrasound,        etc.) that you will use for the implantation procedure.    -   8. Open the package following standard handling procedures and        place the delivery catheters on a clean or sterile field per        your institution's practices.    -   9. If you are using a guide catheter, advance the delivery        catheter through the guide catheter until the full length of the        retention sleeve is outside of the guide catheter. At the        proximal end check the graduations to determine the approximate        length of the delivery catheter that should protrude from the        guide catheter and optionally use a marker to mark the length.

Implantation Procedure

Anchored transponders may be placed during a standalone procedure or inconjunction with diagnostic bronchoscopy. Implantation should beperformed in an ambulatory procedure area or the operating room. Ifexploring or confirming navigable airways that lead to the plannedimplantation site, use of bronchoscopy forceps (in the closed position)or similar accessories is recommended rather than the anchoredtransponder delivery catheter.

-   -   1. Administer sedation or general anesthesia, consistent with        your institution's practice for bronchoscopic placement of lung        fiducials or other flexible bronchoscopy procedures.    -   2. Carefully open the pouch on the chevron side, remove the hoop        from the pouch and slowly remove the first delivery catheter        from its hoop. During handling of the delivery catheter take        care not to damage the glass capsule of the transponder located        at the distal tip and avoid contact with hard surfaces, and        non-clean and/or non-sterile fields.    -   3. Use a bronchoscope, fluoroscopy and, optionally, a guidance        system to advance the delivery catheter to the first        implantation site. Begin with the most distal location as        recommended in the Implantation Site Recommendations and        Implantation Planning section:

When Implanting Directly Through the Instrument Channel of theBronchoscope Using Fluoroscopic Guidance:

-   -   1. Insert the bronchoscope into the lungs and advance it into        the airway leading to the first implantation site. At the        proximal end of the bronchoscope keep the delivery catheter free        of loops and kinks and avoid pinching the catheter where it        exits the bronchoscope.    -   2. In central airways that have an airway stent, maintain the        end of the bronchoscope in a position beyond the distal end of        the airway stent.    -   3. Advance the pre-loaded delivery catheter through the        bronchoscope's instrument channel until it is visible at the tip        of the bronchoscope.    -   4. Note the position of the tip of the bronchoscope within the        tracheobronchial tree and review the previously obtained CT scan        to determine the path to follow and the approximate distance        from the tip of the bronchoscope to the implantation site.    -   5. Carefully advance the delivery catheter beyond the tip of the        bronchoscope, into the airways leading to the implantation site.    -   6. Use fluoroscopy to confirm that you are advancing toward the        target.    -   7. Monitor the graduations on the proximal end of the delivery        catheter to determine the approximate distance the catheter has        advanced into the airways.    -   8. As needed use fluoroscopy performed from one or more angles        to ensure that the delivery catheter tip is not approaching the        pleural surface.    -   9. When fluoroscopy shows that the delivery catheter tip is near        the implantation site, monitor the level of resistance felt as        you advance the catheter. Resistance will increase when the        delivery catheter is in appropriately sized airways about the        diameter of the 2 mm tip of the delivery catheter. If needed,        retract then advance the delivery catheter to confirm resistance        is not due to airway branching. The distal end of the delivery        catheter is flexible and will bow when it encounters resistance        (the catheter bowing can be monitored by fluoroscopy).    -   10. If it is necessary to remove the bronchoscope rapidly and        unexpectedly while the delivery catheter is in the bronchoscope,        remove the delivery catheter from the bronchoscope and check the        distal end of the delivery catheter before continuing to use it.

When Implanting Using a Guide Catheter and/or Other Guidance SystemBeyond the Visual Range of the Bronchoscope:

-   -   a) Follow the manufacturer's instructions to place the tip of        the guide catheter near the implantation site.    -   b) Advance the delivery catheter through the guide catheter        until the retention sleeve at the tip of the delivery catheter        is fully outside of the guide catheter. At the proximal end of        the guide catheter keep the delivery catheter free of loops and        kinks and avoid pinching the delivery catheter where it exits        the guide catheter.    -   c) The proximal graduations and optional mark made before the        implantation procedure can be used to determine the approximate        relative advancement of the delivery catheter in the guide        sheath.    -   d) Fluoroscopy may be used to confirm that the retention sleeve        is outside of the guide sheath.    -   1. Using fluoroscopy performed on at least two perpendicular        angles, confirm that the distal end of the delivery catheter has        reached an acceptable implantation site (see Implant Site        Recommendations); optionally, use the radiopaque ruler to        estimate that the separations meet the recommendations. If the        target is not visible under fluoroscopy monitor other nearby        landmarks to determine proximity to the target implantation        site.    -   2. After confirming that the anchored transponder on the distal        end of the delivery catheter has reached the implantation site,        withdraw the delivery catheter, and guide catheter if being        used, approximately 1-2 cm while still monitoring the distal tip        under fluoroscopy. Withdrawing the delivery catheter 1-2 cm from        the targeted implantation site provides space in the airway for        the anchored transponder to be deployed, ensuring correct        placement of the anchored transponder and preventing bronchial        injury.    -   3. Release the safety lock on the delivery catheter handle by        sliding the lock towards the plunger.    -   4. While monitoring the deployment under fluoroscopy, deploy the        anchored transponder:        -   a) Consider using cine mode or magnifying the view of the            fluoroscopy images during deployment to improve            visualization.        -   b) Actuate the plunger slowly until the anchored transponder            legs exit the retention sleeve.        -   c) Do not simultaneously actuate the plunger and withdraw            the bronchoscope or delivery catheter. Simultaneous            deployment and withdrawal may result in placing the implant            in a more proximal position or larger airway than planned.        -   d) Stop actuating the plunger when fluoroscopy shows that            the anchored transponder has been released from the            retention sleeve at the distal end of the delivery catheter            (FIG. 9):    -   5. The legs will expand in the airway indicating that the legs        have come into contact with the airway wall.    -   6. A separation between the distal tip of the retention sleeve        and the anchored transponder will be seen.    -   7. The deployment wire will move independently of the anchored        transponder.        -   e) Release the pressure on the plunger and confirm under            fluoroscopy that the anchored transponder and the delivery            catheter are separated. The deployment wire will also            retract either partially or fully into the delivery catheter            when the pressure is released.    -   8. While still monitoring under fluoroscopy, begin withdrawing        the delivery catheter. Confirm under fluoroscopy that the        anchored transponder is fully disengaged from the delivery        catheter    -   9. Withdraw the delivery catheter fully from the bronchoscope.    -   10. Record the frequency indicator from the delivery catheter        (1, 2 or 3) and save or print a fluoroscopic snapshot of the        location of the anchored transponder so that the relative        geometry of the three frequencies can be recorded after all        anchored transponders are implanted.    -   11. Leave the bronchoscope in place so that the next delivery        catheter can be advanced to another implantation site.    -   12. Dispose of the used delivery catheter in the appropriate        biohazard waste container.

Implanting Remaining Anchored Transponders

Repeat the above process to access the next two implantation sites andimplant the remaining two anchored transponders. The most distalanchored transponder should have been implanted first. Continue with thenext most distal and save the final anchored transponder for the mostproximal location.

-   -   1. When advancing the delivery catheter to implant the second        and third anchored transponders, use fluoroscopy to monitor the        proximity of the delivery catheter to the already implanted        anchored transponder(s). Take care not to contact the already        implanted anchored transponder(s) with the delivery catheter.    -   2. Ensure the anchored transponders are implanted in a triangle        around the tumor target and are at least 1 cm but no more than        7.5 cm from each other; optionally, use the radiopaque ruler to        estimate the distance to the tumor target and inter-transponder        separations.    -   3. When all three anchored transponders have been implanted,        remove the bronchoscope from the patient.    -   4. Save or print a posterior-anterior fluoroscopy snapshot        showing the three implanted anchored transponders. Annotate each        anchored transponder with its frequency indicator (1, 2 or 3)        based on the snapshots obtained during implantation. Save or        print an additional fluoroscopy snapshot(s) (for example a        lateral view) if it will help in identifying the relative        geometry of the anchored transponders and their frequencies.    -   5. Provide the final fluoroscopic view with the annotations to        the radiation oncology team.

Mis-Deployed or Dislodged Anchored Transponders

If an anchored transponder is inadvertently mis-deployed or becomesdislodged from its implantation site you may wish to retrieve it oradvance it into a small airway.

When to Consider Addressing a Mis-Deployed or Dislodged AnchoredTransponder

The following are reasons to consider retrieving an anchored transponderor advancing it into a smaller airway:

-   -   1. The mis-deployed anchored transponder is in a larger airway        than intended: Anchored transponders should be placed in small        airways (approximately 2-2.5 mm in diameter). If an anchored        transponder is in a larger airway a higher volume of the lung        may be obstructed.    -   2. The mis-deployed anchored transponder is too far from the        tumor target: Anchored transponders should be placed in small        airways near the tumor target. If you feel that you can safely        advance it closer to the target at the time of implantation        without contacting other anchored transponders you may wish to        do so.    -   3. If the radiation oncologist determines that one anchored        transponder is too far from the tumor target, the remaining two        anchored transponders can still be used for localization.    -   4. The dislodged anchored transponder is causing clinically        relevant symptoms: If at some point throughout the patient's        radiation treatment or subsequent follow-up there is concern        about clinically relevant symptoms consistent with endobronchial        foreign bodies you may wish to address the dislodged anchored        transponder.

Conditions for Retrieval

The following are the recommended conditions for retrieval:

-   -   1. The anchored transponder can be visualized with the        bronchoscope: You must be able to see the anchored transponder        using a bronchoscope that has an instrument channel that can        accommodate forceps or other foreign body retrieval accessories.    -   2. The anchored transponder is in a sufficiently large airway:        The anchored transponder must be located in an airway that is 5        mm or larger in diameter    -   3. Three or fewer legs are engaged: The anchored transponder        must have three or fewer legs engaged in the airway walls.    -   When these conditions are met they should minimize the damage to        the airways that may occur during retrieval. If the conditions        for retrieval are met, review the instructions for retrieval. If        the conditions for retrieval are not met, review the conditions        and instructions for advancing the anchored transponder into a        smaller airway.        Conditions for Advancing into a Smaller Airway    -   1. If the anchored transponder cannot be retrieved: You may wish        to review the conditions for retrieving an anchored transponder        and attempt to retrieve it (if the conditions are met) before        deciding to advance the anchored transponder into a smaller        airway.    -   2. The advanced anchored transponder should not contact any        other anchored transponders: Before advancing an anchored        transponder into small diameter airways, you should confirm        under fluoroscopy that you will not come into contact with any        other anchored transponders when navigating to the anchored        transponder or distally advancing it into an airway.

Instructions for Retrieving Anchored Transponders

Anchored transponders should be retrieved using foreign body retrievaltechniques and tools consistent with other endobronchial foreign bodyretrieval. These instructions assume forceps will be used but theinstructions are relevant for the use of other retrieval devices ortools (e.g. a foreign body retrieval basket). Mild damage to the airwayis possible when retrieving the anchored transponder.

-   -   1. Advance the bronchoscope toward the location of the anchored        transponder to be retrieved. Position the bronchoscope in close        proximity to the anchored transponder. In the case of        mis-deployed anchored transponders the bronchoscope will likely        already be in an appropriate place for retrieval.    -   2. Under direct bronchoscopic visualization, advance the forceps        through the working channel of the bronchoscope until it is        visible beyond the tip of the bronchoscope. Open the forceps and        grab one of the five legs of the anchored transponder. It is not        necessary to attempt to compress any or all of the legs since        retrieval should only be attempted if three or fewer legs have        engaged in the airway walls.    -   3. Once the leg is gripped securely, retract the forceps so that        any legs engaged in the airway wall disengage.    -   4. Once the anchored transponder is free of the airway wall        withdraw the forceps until the anchored transponder is near the        tip of the scope. Do not allow the anchor legs to contact the        end of the bronchoscope to avoid scratching the optical lens at        the end of the bronchoscope.    -   5. Rotate the forceps so that the anchored transponder is        oriented with the legs in the shadow of the bronchoscope (all of        the legs are seen and the anchored transponder is approximately        centered in the field of view of the bronchoscope).    -   6. Keeping the leg of the anchored transponder gripped by the        forceps, retract the bronchoscope and forceps together until all        are removed from the patient.    -   7. While retracting the bronchoscope and forceps monitor the        anchored transponder to ensure that the forceps' grip on the        anchored transponder is not lost and that the legs do not        contact the airway wall.

The localization system can operate with the remaining two anchoredtransponders after an anchored transponder has been retrieved. Thelocalization plan can be created with two transponders or edited toremove the retrieved transponder from the plan if it already exists (inthe case of dislodged anchored transponders).

Instructions for Advancing Anchored Transponders into Small Airways

An anchored transponder can be advanced into small airways when theconditions for anchored transponder retrieval are not met, the anchoredtransponder cannot be retrieved, or you wish to attempt to place amis-deployed anchored transponder closer to an implantation site. Milddamage to the airway is possible when advancing the anchored transponderinto small airways.

-   -   1. Determine what instrument will be used to advance the        mis-deployed or dislodged anchored transponder:        -   a. If you have mis-deployed the anchored transponder and the            tip of the delivery catheter has not been retracted into the            bronchoscope you can use the empty delivery catheter to            advance the anchored transponder to a smaller airway. If the            tip of the delivery catheter has already been retracted into            the bronchoscope, do not advance the now-empty delivery            catheter through the bronchoscope as it could catch on the            inside of the bronchoscope and damage the bronchoscope.        -   b. If the tip of the delivery catheter has been retracted            into the bronchoscope or if you are managing a dislodged            anchored transponder use bronchoscopy forceps or a similar            accessory to advance the anchored transponder to a smaller            airway.    -   2. Advance the bronchoscope toward the location of the anchored        transponder. Position the bronchoscope in close proximity to the        anchored transponder (In the case of mis-deployed anchored        transponders the bronchoscope will likely already be in an        appropriate position for retrieval.)    -   3. Advance the delivery catheter or forceps toward the anchored        transponder. If you are using forceps, keep the forceps closed.    -   4. Using the instrument, make contact with the anchored        transponder and advance the anchored transponder into a smaller        airway.    -   5. While advancing the anchored transponder use fluoroscopic        imaging to monitor the current location and intended final        location of the anchored transponder.    -   6. When advancing anchored transponders distally, avoid using        excessive force, contacting other anchored transponders, or        approaching the pleural surface.    -   7. Assess the final location of the mis-deployed or dislodged        anchored transponder:        -   a. If the final location of the mis-deployed or dislodged            anchored transponder does not meet the implantation site            recommendations that anchored transponder can be disabled in            the patient's localization plan and not used for            localization and tracking; the system can operate using the            remaining two anchored transponders.        -   b. If the final location of the anchored transponder meets            the implantation site recommendations, the anchored            transponder can be used in the localization plan.

I. CONCLUSION

From the foregoing, it will be appreciated that specific embodiments ofthe invention have been described herein for purposes of illustration,but that various modifications may be made without deviating from thespirit and scope of the invention. Accordingly, the invention is notlimited except as by the appended claims. The above description ofillustrated embodiments, including what is described in the Abstract, isnot intended to be exhaustive or to limit the invention to the preciseforms disclosed. Although specific embodiments of and examples aredescribed herein for illustrative purposes, various equivalentmodifications can be made without departing from the spirit and scope ofthe invention, as will be recognized by those skilled in the relevantart. The teachings provided herein of the invention can be applied towireless markers, including gold seeds, not necessarily the exemplaryelectromagnetic transponders generally described above.

Reference throughout this specification to “one embodiment” or “anembodiment” means that a particular feature, structure or characteristicdescribed in connection with the embodiment is included in at least oneembodiment of the present invention. Thus, the appearances of thephrases “in one embodiment” or “in an embodiment” in various placesthroughout this specification are not necessarily all referring to thesame embodiment. Furthermore, the particular features, structures, orcharacteristics may be combined in any suitable manner in one or moreembodiments.

Unless the context requires otherwise, throughout the specification andclaims which follow, the word “comprise” and variations thereof, suchas, “comprises” and “comprising” are to be construed in an open,inclusive sense, which is as “including, but not limited to.”

The various embodiments described above can be combined to providefurther embodiments. All of the U.S. patents, U.S. patent applicationpublications, U.S. patent applications, foreign patents, foreign patentapplications and non-patent publications referred to in thisspecification and/or listed in the Application Data Sheet, areincorporated herein by reference, in their entirety. Aspects of theinvention can be modified, if necessary, to employ systems, catheters,markers and concepts of the various patents, applications andpublications to provide yet further embodiments of the invention.

These and other changes can be made to the invention in light of theabove-detailed description. In general, in the following claims, theterms used should not be construed to limit the invention to thespecific embodiments disclosed in the specification and the claims, butshould be construed to include all markers that operated in accordancewith the claims. Accordingly, the invention is not limited by thedisclosure, but instead its scope is to be determined entirely by thefollowing claims.

1-28. (canceled)
 29. A method of treating a body, the method comprising:deploying a marker into a lumen within a body, wherein the deployingincludes: positioning a catheter in the lumen within the body, moving apush wire having an integral retention device contained in the cathetertoward a distal end of the catheter to engage the marker, spring-loadingthe marker in the catheter, and deploying the marker by moving the pushwire toward the distal end of the catheter or by fixing the push wire inplace and retracting the catheter toward a proximal end of the pushwire; determining a fixed relationship between the marker and atreatment target within the body; tracking at least one of position andmotion of the marker during treatment; interrupting the treatment whenthe at least one of the position and the motion of the marker exceeds apredetermined offset value; and repositioning the body to bring the atleast one of the position and the motion of the marker below the offsetvalue before continuing the treatment.
 30. The method of claim 29,wherein positioning includes passing the catheter, push wire, and markerdown a working channel of a bronchoscope a selected distance fordeployment of the marker into a bronchial lumen of the lung, wherein theworking channel of the bronchoscope is lined with polyethylene liner.31. The method of claim 30 where in the liner aligns the push wire in asubstantial centerline configuration.
 32. The method of claim 29 whereinthe positioning includes passing the catheter, push wire, and markerdown a working channel of a bronchoscope a selected distance fordeployment of the marker in a digestive tract lumen.
 33. The assembly ofclaim 29, wherein positioning includes passing the catheter, push wire,and marker down a working channel of a bronchoscope a selected distancefor deployment of the marker in a cardiovascular system lumen.
 34. Themethod of claim 29, wherein the marker is a leadless marker having atransponder that has a response signal to an external energy source. 35.The method of claim 29, wherein the marker is radiographically opaque.36. The method of claim 29, wherein the marker is a radioactive.
 37. Themethod of claim 29, wherein moving the push wire contained in thecatheter includes depressing an actuator.
 38. The method of claim 37,wherein moving the push wire contained in the catheter includesdepressing an actuator, and wherein the actuator has indicator marksthereon to indicate when each marker has been deployed.
 39. A method oftreating a patient according to a radiation plan, the method comprising:positioning a catheter in a lumen within the patient; deploying a firstmarker at a first location proximate a treatment target within thepatient, wherein deploying the first marker includes moving a push wireof the catheter toward a distal end of the catheter or fixing the pushwire in place and retracting the catheter toward a proximal end of thepush wire; deploying a second marker at a second location proximate thetreatment target within the patient; tracking at least one of position,rotation, and motion of the treatment target, wherein the trackingincludes: collecting at least one of position, rotation, and motion dataof the first and second markers during radiation treatment, andcalculating, in real time, at least one of position, rotation, andmotion of the first and second markers using the at least one of theposition, rotation, and motion data of the first and second markers;interrupting the radiation treatment when the at least one of theposition, rotation, and motion of the first and second markers exceeds apredetermined offset value; realigning the patient to bring the at leastone of the position, rotation, and motion of the first and secondmarkers below the predetermined offset value before continuing theradiation treatment; determining whether to adapt the radiation planbased on at least one of changes in the treatment target and results ofthe radiation plan.
 40. The method of claim 39, further comprising:imaging the first marker, the second marker, and the treatment target;and determining the relative distances between the markers and therelative distances between the markers and the treatment target.
 41. Themethod of claim 39 wherein the first and the second markers are magnetictransponder markers having a circuit configured to be energized by awirelessly transmitted pulsed magnetic field and to wirelessly transmita pulsed magnetic location signal in response to the pulsed magneticfield.
 42. The method of claim 39, further comprising spring-loading thefirst marker in the catheter.
 43. The method of claim 39 whereindeploying the second marker at the second location proximate thetreatment target includes repositioning the catheter to the secondlocation.
 44. The method of claim 39 wherein the catheter is a firstcatheter, and wherein deploying the second marker at the second locationproximate the treatment target includes positioning a second catheter tothe second location.
 45. The method of claim 39 wherein the catheterinclude at least one of a perforation, a crease, and a thinned section,and wherein deploying the first marker further includes applying adeployment force that exceeds a breakaway force of the at least one ofthe perforation, crease, and thinned section of the catheter.
 46. Themethod of claim 39 wherein moving the push wire contained in thecatheter includes depressing an actuator.
 47. The method of claim 39wherein the push wire has an integral retention device contained in thecatheter, and wherein the method further comprises moving the push wiretoward the distal end of the catheter to engage the marker.
 48. Themethod of claim 47 wherein: the first marker includes one or morefasteners; the method further comprises spring-loading the one or morefasteners of the first marker in the catheter; and deploying the firstmarker includes releasing the first marker from the integral retentiondevice of the push wire such that the one or more fasteners of the firstmarker extend radially outward fixing the first marker at the firstlocation.